Heparan sulfate: growth control with a restricted sequence menu

Abstract

The growth and differentiation of cells and their organization into organs and tissues are complex processes, largely determined by the concerted actions of the ECM and small, soluble “effector” proteins in the pericellular milieu. Cells respond to the instructive potential of their microenvironment by means of specialized plasma membrane receptors, which elicit intracellular signals when activated by cognate ECM or soluble peptide ligands. In many receptor systems, ligand binds first to an abundant, low-affinity receptor, which draws the ligand onto the cell surface and then transfers it to a second, high-affinity receptor that transduces the appropriate signal into the cell. The most common and widely acting low-affinity receptors are the heparan sulfate proteoglycans (HSPGs), which play central roles in the reception and modulation of a wide range of growth factors, morphogens, and chemokines (1–3). They also act in combination with membrane integrins to control cell adhesion and migration in the ECM (4). The question arises as to how the structure and properties of the HSPGs enable them to fulfill such diverse and fundamental roles. These issues are the subject of intense experimental study, and a growing body of data has been published on the protein recognition properties of HSPGs and their association with signaling receptor complexes. However, more questions are being raised than problems solved by these analyses, perhaps as a result of the unusual properties of the HS chains that determine the majority of the interactions of PGs with external proteins. HS polysaccharides display a versatility in conformation and orientation of functional groups that permits them to employ different modes of binding with any individual protein or protein complex. Here, I argue that this versatility could offset the need for the controlled synthesis of a vast repertoire of defined sequences for exclusive binding of individual proteins.